Assessment of apolipoprotein E genotype for β-amyloid status prediction

Background: Apolipoprotein E (ApoE) is the major genetic risk factor for sporadic Alzheimer's Disease (AD). Some studies showed a relationship between ApoE4 genotype and the cerebrospinal fluid (CSF) biomarkers (β-amyloid42, p-Tau, t-Tau), as well as with cognitive status. In this sense, it could be interesting to develop an approach to establish amyloid status in a minimally invasive way. Methods: The present study assessed the ApoE genotype in different participant groups (mild cognitive impairment due to AD (MCI-AD), mild/moderate dementia due to AD, MCI not due to AD (MCI not AD), other neurological diseases, healthy participants) (n = 342). Results: As expected, the ApoE4 allele was more prevalent in AD patients, characterized by impairment in CSF β-amyloid42 levels (Aβ +), than in the other groups (Aβ -). In this sense, ApoE4-carrier subjects showed lower CSF levels for β-amyloid42 and higher CSF levels for t-Tau and p-Tau. From this, a multivariate model to predict Aβ status was developed by means of partial least square analysis (PLS) and predictive variables (ApoE genotype, cognitive score, sex, age). This model showed suitable AUC-ROC 0.792 (95% CI, 0.744-0.840) and predictive negative value (81.6%). Conclusion: ApoE genotype could be useful in detecting CSF β-amyloid42 impairment associated with early AD development.

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Are neuropsychiatric symptoms in dementia linked to CSF biomarkers of synaptic and axonal degeneration?

Alzheimer s Research & Therapy ◽

10.1186/s13195-020-00718-y ◽

2020 ◽

Vol 12 (1) ◽

Author(s):

Victor Bloniecki ◽

Henrik Zetterberg ◽

Dag Aarsland ◽

Patrizia Vannini ◽

Hlin Kvartsberg ◽

...

Keyword(s):

Cognitive Impairment ◽

Axonal Degeneration ◽

Neuropsychiatric Symptoms ◽

Underlying Disease ◽

Csf Biomarkers ◽

Neurofilament Light ◽

Csf Levels ◽

Low Levels ◽

T Tau ◽

The Relationship

Abstract Background The underlying disease mechanism of neuropsychiatric symptoms (NPS) in dementia remains unclear. Cerebrospinal fluid (CSF) biomarkers for synaptic and axonal degeneration may provide novel neuropathological information for their occurrence. The aim was to investigate the relationship between NPS and CSF biomarkers for synaptic (neurogranin [Ng], growth-associated protein 43 [GAP-43]) and axonal (neurofilament light [NFL]) injury in patients with dementia. Methods A total of 151 patients (mean age ± SD, 73.5 ± 11.0, females n = 92 [61%]) were included, of which 64 had Alzheimer’s disease (AD) (34 with high NPS, i.e., Neuropsychiatric Inventory (NPI) score > 10 and 30 with low levels of NPS) and 18 were diagnosed with vascular dementia (VaD), 27 with mixed dementia (MIX), 12 with mild cognitive impairment (MCI), and 30 with subjective cognitive impairment (SCI). NPS were primarily assessed using the NPI. CSF samples were analyzed using enzyme-linked immunosorbent assays (ELISAs) for T-tau, P-tau, Aβ1–42, Ng, NFL, and GAP-43. Results No significant differences were seen in the CSF levels of Ng, GAP-43, and NFL between AD patients with high vs low levels of NPS (but almost significantly decreased for Ng in AD patients < 70 years with high NPS, p = 0.06). No significant associations between NPS and CSF biomarkers were seen in AD patients. In VaD (n = 17), negative correlations were found between GAP-43, Ng, NFL, and NPS. Conclusion Our results could suggest that low levels of Ng may be associated with higher severity of NPS early in the AD continuum (age < 70). Furthermore, our data may indicate a potential relationship between the presence of NPS and synaptic as well as axonal degeneration in the setting of VaD pathology.

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Genome-wide association, Mendelian Randomization and polygenic risk score studies converge on a role of β−amyloid and APOE locus in Parkinson disease

10.1101/2020.07.01.20144493 ◽

2020 ◽

Author(s):

Laura Ibanez ◽

Jorge A. Bahena ◽

Chengran Yang ◽

Umber Dube ◽

Fabiana G. Farias ◽

...

Keyword(s):

Quantitative Traits ◽

Mendelian Randomization ◽

Genome Wide Association ◽

Csf Biomarkers ◽

Genetic Modifiers ◽

Polygenic Risk ◽

Genomic Architecture ◽

Genome Wide ◽

Csf Levels ◽

T Tau

AbstractAlpha-Synuclein (α-Syn) is the main protein component of Lewy bodies (LB), the pathological hallmark of Parkinson’s disease (PD). Cerebrospinal fluid (CSF) levels of α-Syn are not currently used as a clinical biomarker but may be a proxy for pathological α-Syn accumulation in the brain. Therefore, identifying genetic modifiers of CSF α-Syn levels could provide insights into the underlying molecular mechanisms leading to PD. However, genetic modifiers of CSF α-Syn levels remain unknown. CSF levels of amyloid beta1-42 (Aβ42), total tau (t-tau), and phosphorylated tau181 (p-tau181) are standard biomarkers for the diagnosis of Alzheimer disease (AD); its use as quantitative traits in genetic studies have provided novel insights into AD pathophysiology. A systematic study of the genomic architecture of CSF biomarkers in PD has not been conducted. Here, genome-wide association studies (GWAS) were performed using CSF biomarker levels as quantitative traits in four PD cases and control cohorts (combined N=1,960). CSF biomarker (α-Syn, Aβ42, t-tau, and p-tau181) levels were significantly lower in PD cases compared with controls. An SNP, proxy for APOE ε4, was associated with CSF Aβ42 levels (effect=-0.5, p=9.2×10−19). Several genome-wide suggestive loci associated with CSF α-Syn, t-tau, or p-tau181 were found. Polygenic risk scores (PRS) were constructed using the latest PD risk meta-analysis (49,731 PD cases and 784,343 controls) and the largest CSF biomarkers GWAS (N=3,146). PRS calculated using META-PD were associated with PD status in the four cohorts included in the present study (p= 2.2×10−16). A highly significant correlation (Nagelkerke pseudo-R2 =2.29%; p=2.5×10−11) of the genomic architecture between CSF Aβ42 and PD risk was also found. Higher PRS scores were associated with lower CSF Aβ42 levels (p=7.3×10−04). Two-sample Mendelian Randomization (MR) approach revealed that CSF Aβ42 plays a role in PD risk (p=1.4×10−05) and age at onset (p=7.6×10−06), an effect mainly mediated by variants in the APOE locus. Subsequently, the APOE ε4 allele was associated with significantly lower levels of CSF Aβ42 (p=3.8×10−06), higher mean cortical binding potentials (cortical binding of Pittsburgh compound B PET) (p=5.8×10−08) and higher Braak Aβ score (p=4.4×10−04) in PD participants. Together these results from high-throughput and hypothesis-free approaches (GWAS, PRS and MR) converge on a genetic link between PD with CSF Aβ42 and APOE.

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CSF Biomarkers Profile in CADASIL—A Model of Pure Vascular Dementia: Usefulness in Differential Diagnosis in the Dementia Disorder

International Journal of Alzheimer s Disease ◽

10.4061/2010/959257 ◽

2010 ◽

Vol 2010 ◽

pp. 1-6 ◽

Cited By ~ 7

Author(s):

Patrizia Formichi ◽

Lucilla Parnetti ◽

Elena Radi ◽

Gabriele Cevenini ◽

Maria Teresa Dotti ◽

...

Keyword(s):

Differential Diagnosis ◽

Vascular Dementia ◽

Tau Protein ◽

Autosomal Dominant ◽

Case Control ◽

Csf Biomarkers ◽

Total Tau ◽

Csf Levels ◽

T Tau ◽

Phosphorylated Tau Protein

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is considered a model of pure vascular dementia (VD) because it occurs in young adults unlikely to have concomitant age and Alzheimer's Disease-(AD-) related pathology. CSF levels of -amyloid 1-42 (A42), total tau protein (t-tau), and phosphorylated tau-protein (p-tau), well accepted biomarkers of AD, were evaluated in 10 CADASIL patients, 22 AD patients, and 17 healthy age-matched subjects. Innotest -amyloid 1-42, Innotest hTAU-Ag, and Innotest Phospho-tau 181p sandwich enzyme-linked immunoassay were used to determine CSF biomarkers levels. A case-control statistical analysis was carried out. CSF A42 levels were significantly lower in CADASIL patients and considerable overlap with AD whereas t-tau and p-tau levels were normal and significantly different with respect to AD. A significant altered CSF biomarkers profile in a pure VD supports the use of CSF A42, t-tau, and p-tau levels in the differential diagnosis of VD and AD.

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Influence of APOE Genotype on Alzheimer’s Disease CSF Biomarkers in a Spanish Population

BioMed Research International ◽

10.1155/2016/1390620 ◽

2016 ◽

Vol 2016 ◽

pp. 1-7 ◽

Cited By ~ 4

Author(s):

J. A. Monge-Argilés ◽

R. Gasparini-Berenguer ◽

M. Gutierrez-Agulló ◽

C. Muñoz-Ruiz ◽

J. Sánchez-Payá ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Apoe Genotype ◽

Amnestic Mild Cognitive Impairment ◽

Spanish Population ◽

Csf Biomarkers ◽

Csf Levels

Objectives. To evaluate the association between apolipoprotein E (APOE) genotype and cerebrospinal fluid (CSF) levels of Alzheimer’s disease (AD) biomarkers and to study the influence of APOE genotype on the development of AD in a Spanish population.Material and Methods. The study comprised 29 amnestic mild cognitive impairment (MCI) patients and 27 control subjects. Using ELISA methodology, CSF biomarkers and tau/Aβratios were obtained. ANOVA and adjusted odds ratios were calculated.Results. We observed the effect of APOE genotype and age on CSF AD variables. The progression to AD was more clearly influenced by CSF AD variables than by age or APOE status.Conclusions. APOE status influences CSF AD variables. However, the presence of APOEε4 does not appear to be a deterministic factor for the development of AD, because CSF variables have a greater influence on progression to the disease. These results confirm previous observations and, to our knowledge, are the first published in a Spanish population.

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Diagnostic Validity Comparison Between Criteria Based on CSF Alzheimer’s Disease Biomarkers

American Journal of Alzheimer s Disease & Other Dementias® ◽

10.1177/1533317516688298 ◽

2017 ◽

Vol 32 (2) ◽

pp. 101-107 ◽

Cited By ~ 2

Author(s):

Maria Empar Blanco-Cantó ◽

J. A. Monge-Argilés ◽

C. Pérez-Cejuela ◽

C. Badía ◽

L. Gabaldón ◽

...

Keyword(s):

Cognitive Impairment ◽

Csf Biomarkers ◽

Diagnostic Validity ◽

High Likelihood ◽

Disease Biomarkers ◽

Csf Levels ◽

T Tau ◽

New Criteria ◽

Mci Due To Ad

Aim: To compare the diagnostic validity of NIA-AA criteria, for AD CSF biomarkers, with our own new criteria. Materials and Methods: Between 2008 and 2011, 170 patients with Mild Cognitive Impairment (MCI) were included. CSF levels of Aβ1-42, T-tau, P-tau181, and ratios of T-tau/Aβ1-42 and P-tau181/Aβ1-42 were analyzed. In our criteria, we considered 3 or more abnormal variables indicative of a high likelihood of MCI due to AD. Results: After a clinical follow-up of 4.5 ± 1.2 years, 44 patients remained stable, 95 developed AD, 15 other forms of dementia, 7 died and 9 received other diagnoses. Using the NIA-AA criteria and our own criteria, the diagnostic validity of the CSF biomarkers was 58% versus 85%, specificity 84% versus 72%, PPV 82% versus 79% and NPV 61% versus 79%. Conclusion: The inclusion of the ratios in diagnostic criteria increases sensitivity and NPV for the diagnosis of MCI due to AD.

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Role of cerebrospinal fluid biomarkers to predict conversion to dementia in patients with mild cognitive impairment: a clinical cohort study

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2014-0414 ◽

2015 ◽

Vol 53 (3) ◽

Cited By ~ 7

Author(s):

Manuela Tondelli ◽

Roberta Bedin ◽

Annalisa Chiari ◽

Maria Angela Molinari ◽

Guendalina Bonifacio ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Csf Biomarkers ◽

Neuropsychological Evaluation ◽

Neurological Assessment ◽

Blood Tests ◽

Clinical Cohort ◽

Cerebrospinal Fluid Biomarkers ◽

Csf Levels ◽

T Tau

AbstractCerebrospinal fluid (CSF) levels assessment of AβA group of 71 MCI patients underwent neurological assessment, extended neuropsychological evaluation, routine blood tests, ApoE determination, and lumbar puncture to dose t-tau, p-tauBaseline AβOur results confirm the key role of CSF biomarkers in predicting patient conversion from MCI to dementia. The study suggests that CSF biomarkers may also be reliable in a real world clinical setting.

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Time Trends of Cerebrospinal Fluid Biomarkers of Neurodegeneration in Idiopathic Normal Pressure Hydrocephalus

Journal of Alzheimer s Disease ◽

10.3233/jad-201361 ◽

2021 ◽

Vol 80 (4) ◽

pp. 1629-1642

Author(s):

Heikki Lukkarinen ◽

Ina Tesseur ◽

Darrel Pemberton ◽

Peter Van Der Ark ◽

Maarten Timmers ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Normal Pressure Hydrocephalus ◽

Apoe Genotype ◽

Brain Biopsy ◽

Normal Pressure ◽

Idiopathic Normal Pressure Hydrocephalus ◽

Csf Shunt ◽

Csf Biomarkers ◽

Post Surgery ◽

T Tau

Background: Longitudinal changes in cerebrospinal fluid (CSF) biomarkers are seldom studied. Furthermore, data on biomarker gradient between lumbar (L-) and ventricular (V-) compartments seems to be discordant. Objective: To examine alteration of CSF biomarkers reflecting Alzheimer’s disease (AD)-related amyloid-β (Aβ) aggregation, tau pathology, neurodegeneration, and early synaptic degeneration by CSF shunt surgery in idiopathic normal pressure hydrocephalus (iNPH) in relation to AD-related changes in brain biopsy. In addition, biomarker levels in L- and V-CSF were compared. Methods: L-CSF was collected prior to shunt placement and, together with V-CSF, 3–73 months after surgery. Thereafter, additional CSF sampling took place at 3, 6, and 18 months after the baseline sample from 26 iNPH patients with confirmed Aβ plaques in frontal cortical brain biopsy and 13 iNPH patients without Aβ pathology. CSF Amyloid-β42 (Aβ42), total tau (T-tau), phosphorylated tau (P-tau181), neurofilament light (NFL), and neurogranin (NRGN) were analyzed with customized ELISAs. Results: All biomarkers but Aβ42 increased notably by 140–810% in L-CSF after CSF diversion and then stabilized. Aβ42 instead showed divergent longitudinal decrease between Aβ-positive and -negative patients in L-CSF, and thereafter increase in Aβ-negative iNPH patients in both L- and V-CSF. All five biomarkers correlated highly between V-CSF and L-CSF (Aβ42 R = 0.87, T-tau R = 0.83, P-tau R = 0.92, NFL R = 0.94, NRGN R = 0.9; all p < 0.0001) but were systematically lower in V-CSF (Aβ42 14 %, T-tau 22%, P-tau 20%, NFL 32%, NRGN 19%). With APOE genotype-grouping, only Aβ42 showed higher concentration in non-carriers of allele ɛ4. Conclusion: Longitudinal follow up shows that after an initial post-surgery increase, T-tau, P-tau, and NRGN are stable in iNPH patients regardless of brain biopsy Aβ pathology, while NFL normalized toward its pre-shunt levels. Aβ42 as biomarker seems to be the least affected by the surgical procedure or shunt and may be the best predictor of AD risk in iNPH patients. All biomarker concentrations were lower in V- than L-CSF yet showing strong correlations.

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The Relationship Between Neuropsychiatric Symptoms, Nighttime Behaviors, and Alzheimer’s Disease CSF Biomarkers

Innovation in Aging ◽

10.1093/geroni/igab046.2463 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. 655-656

Author(s):

Meina Zhang ◽

Young-Eun Cho ◽

Chooza Moon

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Impairment ◽

Sleep Disturbances ◽

Linear Models ◽

Neuropsychiatric Symptoms ◽

Cognitive Status ◽

Csf Biomarkers ◽

T Tau ◽

The Relationship

Abstract Alzheimer's disease (AD) commonly involves neuropsychiatric symptoms (NPS), such as nighttime behaviors (or sleep disturbance), hallucination, delusion, or mood changes. However, it is unclear how NPS and sleep disturbances are correlated with AD biomarkers. The purpose of this analysis was to examine how NPS and nighttime behaviors are associated with AD CSF biomarkers by cognitive status. A total of 1,667 subjects’ (mean age = 69.4 SD=9.3, 48 % (808) were male) data from the National Alzheimer’s Disease Coordinating Center (NACC) were used, including subjects with dementia (n = 577), mild cognitive impairment (MCI, n = 363), cognitive impairment but not MCI (n = 47), cognitive impairment due to Alzheimer’s etiology (n= 608), and normal cognition (n = 680). The nighttime symptoms, number, and severity of NPS were assessed using the Neuropsychiatric Inventory Questionnaire Quick Version (NPI-Q). Cerebrospinal fluid (CSF) samples were analyzed for Aβ42,dft5 t-tau, p-tau. We used generalized linear models to explore the associations accounting for age, sex, APOE4 alleles, and BMI. We found the number of NPS were associated with Aβ42 (p = 0.042) in individuals with MCI, impaired, or dementia due to Alzheimer’s etiology. Yet, the number of NPS were not associated with t-tau or p-tau in individuals with and without dementia. The severity of NPS including nighttime symptoms were not associated with biomarkers. Our results could suggest that the number of NPS can be reflected by higher CSF Aβ42 levels in the individuals with Alzheimer’s etiology. Future longitudinal analyses are warranted to understand the causal relationships.

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Higher Level of Mismatch in APOEε4 Carriers for Amyloid-Beta Peptide Alzheimer’s Disease Biomarkers in Cerebrospinal Fluid

ASN NEURO ◽

10.1177/1759091419845524 ◽

2019 ◽

Vol 11 ◽

pp. 175909141984552 ◽

Cited By ~ 2

Author(s):

Jonathan Vogelgsang ◽

Ruth Vukovich ◽

Dirk Wedekind ◽

Jens Wiltfang

Keyword(s):

Cerebrospinal Fluid ◽

Amyloid Beta ◽

Apoe Genotype ◽

Csf Biomarkers ◽

Disease Biomarkers ◽

Apoe Ε4 ◽

Beta Peptide ◽

Diagnosis Of Dementia ◽

Csf Levels ◽

Dementia Diagnostics

Cerebrospinal fluid (CSF) biomarkers are widely used in the diagnosis of dementia. Even though there is a causal correlation between apolipoprotein E ( APOE) genotype and amyloid-beta (Aβ), the determination of APOE is currently not supported by national or international guidelines. We compared parallel measured CSF biomarkers of two independent laboratories from 126 patients who underwent clinical dementia diagnostics regarding the APOE genotype. APOE ε4 reduces Aβ1-42 (Aβ42) and Aβ42 to Aβ 1-40 ratio (Aβ42/40) but not total Tau or phospho-181 Tau CSF levels. Higher discordance rates were observed for Aβ42 and subsequently for Aβ42/40 in APOE ε4 carriers compared with noncarriers, and the correlation between the two laboratories was significantly lower for Aβ42 in APOE ε4 positive patients compared with patients without APOE ε4. These observations demonstrate that the evaluation of CSF Aβ biomarkers needs to be interpreted carefully in the clinical context. Different immunoassays, disparate cutoff values, and APOE should be respected.

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Interaction Between APOE Genotype and Diabetes in Longevity

Journal of Alzheimer s Disease ◽

10.3233/jad-210125 ◽

2021 ◽

pp. 1-8

Author(s):

Mitsuru Shinohara ◽

Kaoru Suzuki ◽

Guojun Bu ◽

Naoyuki Sato

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Apolipoprotein E ◽

Interactive Effect ◽

Apoe Genotype ◽

Potential Interaction ◽

Cognitive Status ◽

Diabetic Status ◽

Clinical Records ◽

Harmful Effects

Background: While both apolipoprotein E (APOE) genotype and diabetes affect longevity as well as Alzheimer’s disease, their relationship remains to be elucidated. Objective: The current study investigated the potential interaction between diabetes and APOE for lifespan and their relationship with cognitive status. Methods: We reviewed the National Alzheimer’s Coordinating Center (NACC) dataset, which documents longitudinally clinical records of 24,967 individuals with APOE genotype and diabetic status. Results: Diabetes was associated with shorter lifespan in APOE3 carriers (n = 12,415, HR = 1.29, 95%CI = 1.17–1.42, p < 0.001) and APOE2 carriers (n = 2,390, HR = 1.37, 95%CI = 1.10–1.69, p = 0.016), while such associations were weaker and not significant in APOE4 carriers (n = 9,490, HR = 1.11, 95%CI = 0.99–1.24, p = 0.162). As there is a significant interactive effect of cognitive status and diabetes on lifespan (p < 0.001), we stratified subjects by cognitive status and observed persistent APOE-dependent harmful effects of diabetes in nondemented individuals but not demented individuals. Notably, questionnaire-based activity status, with which we previously observed an association between APOE genotype and longevity, was also significantly affected by diabetes only in non-APOE4 carriers. Conclusion: The effects of diabetes on longevity vary among APOE genotype. These effects are observed in nondemented individuals and are potentially associated with activity status during their lifespan.

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